Abstract
For treatment of critical heart valve diseases, prosthetic valves perform fairly well in most adults; however, for pediatric patients, there is the added requirement that the replacement valve grows with the child, thus extremely limiting current treatment options. Tissue engineered heart valves (TEHV), such as those derived from autologous bone marrow stem cells (BMSCs), have the potential to recapitulate native valve architecture and accommodate somatic growth. However, a fundamental pre-cursor in promoting directed integration with native tissues rather than random, uncontrolled growth requires an understanding of BMSC mechanobiological responses to valve-relevant mechanical environments. Here, we report on the responses of human BMSC-seeded polymer constructs to the valve-relevant stress states of: (i) steady flow alone, (ii) cyclic flexure alone, and (iii) the combination of cyclic flexure and steady flow (flex-flow). BMSCs were seeded onto a PGA: PLLA polymer scaffold and cultured in static culture for 8 days. Subsequently, the aforementioned mechanical conditions, (groups consisting of steady flow alone—850ml/min, cyclic flexure alone—1 Hz, and flex-flow—850ml/min and 1 Hz) were applied for an additional two weeks. We found samples from the flex-flow group exhibited a valve-like distribution of cells that expressed endothelial (preference to the surfaces) and myofibroblast (preference to the intermediate region) phenotypes. We interpret that this was likely due to the presence of both appreciable fluid-induced shear stress magnitudes and oscillatory shear stresses, which were concomitantly imparted onto the samples. These results indicate that flex-flow mechanical environments support directed in vitro differentiation of BMSCs uniquely towards a heart valve phenotype, as evident by cellular distribution and expression of specific gene markers. A priori guidance of BMSC-derived, engineered tissue growth under flex-flow conditions may serve to subsequently promote controlled, engineered to native tissue integration processes in vivo necessary for successful long-term valve remodeling.
Highlights
Heart valves play an important role in controlling unidirectional blood flow
Bioreactors have been built to couple any combination of flow, cyclic stretch and cyclic flexure (FSF bioreactors), which have verified that coupled mechanical stimuli significantly promote extracellular matrix (ECM) production; in particular, the combination of steady flow with cyclic flexure [9,10] relevant to heart valves, Vermot et al showed that blood flow-induced oscillatory shear stresses (OSS) directly modulate the normal expression of a transcription factor from the kruppel-like factor gene family, KLF2A, in a zebra fish model
Towards the tissue engineering of heart valves, we examined how flexure and/or steady flow modes of mechanical stimuli at physiologically relevant scales can promote collagen content in the de novo tissues derived from bone marrow stem cells (BMSCs)
Summary
Heart valves play an important role in controlling unidirectional blood flow. birth defects or infections (e.g. rheumatic fever) can cause one or more of the heart valves to malfunction, which may lead to critical valve anomalies in children. Native valves are continuously subjected to mechanical stress as a result of blood flow; for example, aortic valve leaflets experience peak fluid-induced shear stresses of approximately 5–6 dyne/cm in mid systole [2,3,4]. In an engineered heart valve tissue context, mechanical stimuli, those that incorporated fluid-induced shear stress, have enhanced progenitor cell differentiation pathways and construct tissue properties for the valve application [5,6,7,8]. Bioreactors have been built to couple any combination of flow, cyclic stretch and cyclic flexure (FSF bioreactors), which have verified that coupled mechanical stimuli significantly promote ECM production; in particular, the combination of steady flow with cyclic flexure [9,10] relevant to heart valves, Vermot et al showed that blood flow-induced oscillatory shear stresses (OSS) directly modulate the normal expression of a transcription factor from the kruppel-like factor gene family, KLF2A, in a zebra fish model. The KLF2A gene is critically involved in valvulogenesis, whose absence results in defective heart valves [11]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
